The orderly tranport of proteins within the secretory pathway of eucaryotic cells is mediated by the specific recognition and fusion of transport vesicles with distinct target organelle-associated membrane proteins termed syntaxins. In our attempt to identify the transport route taken by newly synthesized MHC class II-invariant chain complexes to intracellular antigen processing compartments, we have screened a human B cell cDNA library for endosome/lysosome-specific syntaxins. Our initial experiments resulted in the isolation of a full-length cDNA clone encoding human syntaxin 5, a transmembrane protein whose rat and yeast homologs regulate endoplasmic reticulum- to-Golgi apparatus transport. In our attempt to identify the proteins responsible for the recognition of these newly synthesized MHC class II glycoproteins, we are probing a human B lymphocyte cDNA library with a human invariant chain cytosolic tail "bait" using the yeast two-hybrid system. Although we have not yet identified the nature of these genes, we expect that this analysis will allow us to further understand the molecular mechanisms underlying antigen processing and presentation by MHC class II molecules.